The cerebellum is a highly conserved brain structure involved in motor learning and behavior. The aim of this research proposal is to elucidate the cellular mechanisms underlying synaptic plasticity in the cerebellar nuclei, the output of the cerebellum. This research will support the broader long-term goal of understanding the cellular mechanisms of learning and memory in cerebellum-dependent behaviors. Lesion studies suggest that the nuclei are a locus of learning and memory which specifically involve mossy fiber afferents carrying sensory information. We propose to investigate how two disparate forms of mossy fiber synaptic plasticity - potentiation and depression - are coordinated at the level of single neurons. These opposing forms of synaptic plasticity are generated following afferent stimulation patterns that differ only slightly, and thus likely converge on at least partly the same signaling pathways. Specifically, potentiation follows coincident excitation and inhibition while depression occurs after excitation alone. The requirement for inhibition in the potentiation protocol sets this form of plasticity apart from others investigated elsewhere in the brain and therefore promises to broaden our understanding of how synaptic plasticity is generated across different neuronal cell types. Our specific aims target h/vo levels of mechanistic organization: enzymatic signaling and transmitter receptor delivery to synapses. Whole cell voltage- and current-clamp recordings are made from neurons in an acute mouse brain slice preparation and electrical stimulation is used to elicit synaptic currents. Various pharmacological agents will be used to test the roles of molecular cascades mediating plasticity. PUBLIC HEALTH RELEVANCE: Several human pathologies are linked to cerebellar dysfunction such as ataxias, dystonias, autism and some forms of mental retardation. Understanding how cerebellar circuitry supports healthy behavior is essential to decipher the roots of neural pathologies. By targeting specific enzymes and proteins involved in a cellular function that likely underlies behavior, we lay the groundwork for linking gene mutations to observable pathologies.